The goal of this proposal is to examine the role of prostate stem cell antigen (PSCA) in the prognosis and therapy of prostate cancer. PSCA is a cell surface antigen, which is overexpressed in approximately 40 percent of primary prostate cancers and in as many as 100 percent of metastatic ones. PSCA is also overexpressed in a majority of transitional cell and pancreatic carcinomas. Overexpression of PSCA in prostate cancer correlates with adverse clinicopathologic features, including advanced tumor stage, grade and MYC amplification. A monoclonal antibody directed against PSCA inhibits tumorigenesis, slows tumor growth, prolongs survival and prevents metastasis in a preclinical xenograft model. These data suggest that PSCA may have utility as a prognostic marker and/or therapeutic target in prostate cancer. The overall goals of this project are to determine the prognostic utility of PSCA in patients with clinically localized prostate cancer and to understand and enhance the therapeutic utility of monoclonal antibodies directed against this target. Finally, we intend to translate the knowledge gained from preclinical evaluation of PSCA as a prognostic and therapeutic target into a pilot human clinical trial in which we ask whether PSCA monoclonal antibodies are safe and can localize to PSCA-overexpressing tumors in high-risk individuals undergoing radical prostatectorny. These studies are expected to lead to larger clinical trials examining the therapeutic efficacy of PSCA antibodies.